Parkinson's disease (PD) is the most common neurodegenerative movement disorder, affecting 1-4% of the population above the age of 65. To date, the cause for the majority of patients with PD is unknown and the cellular pathways implicated are ill-defined. The risk for PD diagnosis increases with age. Thus, with an increasingly aging population, it becomes necessary to better understand PD pathogenesis. Due to genetic defects, a paucity of a protein called DJ-1 can lead to Parkinson's disease in some patients. The overall goal of the project is to identify the cellular role(s) of DJ-1 and its relationships to other proteins, Parkin and alpha-Synuclein, which are also directly implicated in Parkinson's disease. In this proposal, the ability of DJ-1 to regulate Parkin expression and the mechanism(s) involved in the process will be assessed. The biological activities of DJ-1 and effects of the loss thereof due to disease-causing mutations will be investigated. It also is proposed that novel modifications of DJ-1 will be identified, as they may provide insights into the function of DJ-1. The ability of DJ-1 to suppress alpha-Synuclein aggregation, which is involved in pathobiology of Parkinson's disease, will also be assessed in vivo. These studies will be conducted by using cell culture systems and transgenic mouse models of the human disease. The completion of these studies will provide a better understanding of the biological function of DJ-1 and its interplay with other specific proteins such as Parkin and alpha-Synuclein in defining biological pathways involved in the pathobiology of PD.